Regulation of metalloproteinases and NF-kappaB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA

Br J Pharmacol. 2004 Jul;142(6):973-82. doi: 10.1038/sj.bjp.0705864. Epub 2004 Jun 21.

Abstract

1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alprostadil / metabolism
  • Analysis of Variance
  • Animals
  • Butadienes / pharmacology
  • Butanones / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprost / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Imidazoles / pharmacology
  • Interleukin-1 / pharmacology
  • Matrix Metalloproteinase 1 / metabolism
  • Metalloendopeptidases / metabolism*
  • NF-kappa B / metabolism*
  • Nabumetone
  • Naphthaleneacetic Acids / pharmacology
  • Nitric Oxide / biosynthesis
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Prostaglandins E / metabolism*
  • Pyridines / pharmacology
  • Rabbits
  • Synovial Membrane / cytology
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Butadienes
  • Butanones
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-1
  • NF-kappa B
  • Naphthaleneacetic Acids
  • Nitriles
  • Prostaglandins E
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • U 0126
  • Nitric Oxide
  • 6-methoxy-2-naphthylacetic acid
  • Dinoprost
  • Extracellular Signal-Regulated MAP Kinases
  • Metalloendopeptidases
  • Matrix Metalloproteinase 1
  • Alprostadil
  • Nabumetone
  • SB 203580